MOLECULAR EPIDEMIOLOGY OF HIV-ASSOCIATED CANCERS Release Date: April 6, 2000 PA NUMBER: PA-00-086 National Cancer Institute National Institute of Dental and Craniofacial Research THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. This Program Announcement (PA) replaces PA-97-057, which was published in NIH Guide Volume 26, Number 13, April 25, 1997. PURPOSE The Division of Cancer Control and Population Sciences of the National Cancer Institute (NCI) and the National Institute of Dental and Craniofacial Research (NIDCR) invite grant applications for interdisciplinary studies to better understand the molecular epidemiology and role of cofactors in the etiology of pre-neoplastic conditions and cancers occurring among persons infected with the human immunodeficiency virus (HIV), specifically those cancers associated with the DNA viruses, including human papilloma virus (HPV), Epstein Barr virus (EBV), and human herpes virus 8/Kaposi’s sarcoma associated herpes virus (HHV8/KSHV). Cofactors of keen interest to the NCI include host genetic susceptibility and phenotype, age at first acquisition of the oncogenic virus, temporal association of acquisition of the oncogenic virus relative to time of HIV acquisition, effect of circulating viral load of the oncogenic virus, measurements of immune response, and role of behavioral factors such as tobacco use and diet. It is expected that enhanced understanding of the molecular epidemiology of these tumors within the context of HIV-induced host immunodeficiency will yield information important to cancer control and prevention, including development of prophylactic vaccines, chemotherapeutic treatment modalities, other biomedical, and behavioral preventive interventions. The NIDCR is principally interested in applying molecular epidemiology and the role of co- factors in the etiology of perineoplastic lesions these DNA viruses cause in the oral cavity of the immune compromised host. These lesions usually occur in the oral cavity, early in acute HIV infection and are reestablished when immune incompetency is a fact. This PA will expire in two years from the first receipt date. NIH Grants policies apply to these awards. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA, Molecular Epidemiology of HIV-Associated Cancers, is related to the priority areas of cancer and HIV infection. Potential applicants may obtain a copy of "Healthy People 2010" at ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. The total requested project period for an application submitted in response to the PA may not exceed five years. Foreign applications will receive no support for indirect costs. Domestic applications may include international components but these components will receive no support for indirect costs. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) and competing supplements to existing NCI and NIDCR funded (R01) grants. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. In the case of competing supplements to existing grants, applicants will be required to obtain and attach to their applications a document indicating that the submission of their application has been approved by the Principal Investigator of the research project grant. This will be especially important if the application will require access to biological specimens from a central repository or to existing databases. Competing supplements must not extend beyond the funding period of the parent grant, the parent grant must have at least one year remaining in its project period after award of the supplement. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at RESEARCH OBJECTIVES Background Infection by the human retrovirus, HIV, is a major public health problem throughout the world, particularly in the developing world. Retroviruses may be directly oncogenic, or may foster the development of human cancers indirectly through immune suppression and subsequent reactivation of previously latent human oncogenic viruses. The young age at which most people in the world become infected with HIV coupled with time spent living in an immunodeficient state portends that retroviral-associated cancers will impose a greater impact of years of potential life lost and quality of life than other cancers. The NCI and NIDCR have had a continuing interest in the study of the molecular epidemiology of pre-neoplastic conditions and cancers occurring among HIV-infected persons. Some cancers, notably those associated with oncogenic human DNA viruses of the lymphoreticular system (non-Hodgkin’s lymphoma, Hodgkin’s Disease), soft tissue (Kaposi’s sarcoma,) and epithelial tissues (anogenital dysplasias and cancers) are significantly increased in incidence, display an aggressive pattern of development and progression in HIV-infected individuals, and/or remain refractory to standard therapies. It is expected that enhanced understanding of the molecular epidemiology of these tumors within the context of HIV-induced host immunodeficiency will yield information important to cancer control and prevention, including development of prophylactic vaccines, chemotherapeutic treatment modalities, and other biomedical preventive interventions. The cancers of interest in this PA are ones associated with concomitant infection with DNA viruses that frequently confer latency, such as Epstein Barr virus (EBV), human herpes virus 8/Kaposi’s sarcoma associated herpes virus (HHV8/KSHV) and human papilloma virus (HPV). In each case, infection by the concomitant virus appears to be necessary for subsequent oncogenesis, but not sufficient to lead to cancer in every case. Therefore, both endogenous and exogenous cofactors must play a significant role. For this PA, cofactors of special interest include host genetic susceptibility and phenotype, age at first acquisition of the oncogenic virus, temporal association of acquisition of the oncogenic virus relative to time of HIV acquisition, effect of circulating viral load of the oncogenic virus, measurements of immune response, and role of behavioral factors such as tobacco use and diet. This PA seeks to encourage research on the molecular and social epidemiology of preneoplastic conditions among HIV infected persons throughout the world and comparative epidemiologic studies based in several geographic areas. An interdisciplinary approach that links the expertise of basic scientists with that of epidemiologists, clinicians, and behavioral scientists in an etiologic study is strongly encouraged. Investigations may be conducted in adults and/or children. The areas of research listed below are not intended to be all inclusive, but are designed to give the applicant some direction as to the types of research that the NCI is interested in stimulating. The NIDCR is interested in the areas of research listed with special focus on oral viral sentinel lesions and how these may affect HIV progression to AIDS. o The (treated) natural history of cancers and pre-neoplastic changes in situations where the temporality of observed events, including timing of first infection or reactivation of existing infection, may be addressed o The interplay of route of acquisition of the DNA virus, particularly HHV8/KSHV, and other cofactors on the molecular epidemiology and natural history of oncogenesis o The role of host genetic susceptibility on the molecular epidemiology of these tumors o The effect of the age of first acquisition of the oncogenic virus, particularly with regards to the temporal association with acquisition of HIV o The relationships of levels of circulating viral load of the oncogenic virus and of HIV, and the effects on the natural history of both HIV disease and oncogenesis o The temporal relationships of immune markers measured both qualitatively and quantitatively with other variables of interest in the epidemiology of these tumors o The effect of past and current use of recreational drugs, including alcohol, on the epidemiology of these tumors o The role of diet, nutrition, and dietary supplements, both before acquisition of the viruses and after the recognition of infection, on the epidemiology of these tumors o The effect of past and current use of tobacco products on the epidemiology of these tumors, including the relationships among nicotine biomarkers, measures of immune function, and circulating viral load o The role of psychosocial processes in infection and disease detection and progression INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should follow the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18, 1994, Volume 23, Number 11, available on the web at the following URL address: INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: For those applicants with internet access, the 398 kit may be found at: Applicants are strongly encouraged to call the program contacts listed in INQUIRIES below with any questions. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see for sample pages). At the top of the page, enter the total direct costs requested for each year. This is not a form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is domestic or foreign. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The number and title of the PA must be typed on line 2 of the face page of the application and the YES box must be marked. Submit a signed, typewritten original of the application, including the checklist, and five signed, exact, single-sided photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed assigned a priority score, and receive a second level review by the appropriate national advisory board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Approach: Are the conceptual framework, design, methods, and analyzes adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigator: is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support ? The initial review group will also examine: the adequacy of plans to include both genders and minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and programmatic priority. INQUIRIES Inquiries concerning this PA are encouraged, particularly during the planning phase of the grant applications. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding overall programmatic issues to: Dr. Sandra L. Melnick or Vaurice Starks Division of Cancer Control and Population Sciences National Cancer Institute Executive Plaza North, Room 240, MSC 7395 Bethesda, MD 20892-7395 Telephone: (301) 402-9375 FAX: (301) 402-4279 Email: Direct inquiries regarding applications with a primary focus on behavioral science to: Dr. Wendy Nelson Division of Cancer Control and Population Sciences National Cancer Institute Executive Plaza North, Room 4064, MSC 7326 Bethesda, MD 20892-7326 Telephone: (301) 435-4590 FAX: (301) 435-7547 Email: Direct inquiries regarding application with a primary focus on oral health to: Denise Anne Russo, Ph.D. Infectious Diseases and Immunity Branch Division of Extramural Research, National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-18B Bethesda, MD 20892-6402 Telephone: (301) 594-2617 FAX: (301) 480-8318 Email: Direct inquiries regarding fiscal matters to: Bill Wells Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 6120 Executive Blvd. Bethesda, MD, 20892 Tel: 301-496-8796 Fax: 301-496-8601 Email: Mr. Kevin Crist Grants Management Branch Division of Extramural Research National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-38B, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-4800 FAX: (301) 480-8301 Email: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.393, 93.856, and 93.121. Awards are made under authorization Sections 301 and 405 of the Public Health Service Act amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a Health Systems Agency Review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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